Neuroscience and Biobehavioral Reviews · The symptoms we identify and the behaviors we recognize as defenses deﬁne which symptoms we see as trauma-related. Early conceptions of

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Neuroscience and Biobehavioral Reviews 37 (2013) 1549–1566

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

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rimitive mechanisms of trauma response: An evolutionaryerspective on trauma-related disorders

avid V. Baldwin ∗

ndependent Practice, PO Box 11143, Eugene, OR 97440, USA

r t i c l e i n f o

rticle history:eceived 29 November 2012eceived in revised form 23 May 2013ccepted 3 June 2013

eywords:efensive behaviorynamic systemsmotional trauma

a b s t r a c t

The symptoms we identify and the behaviors we recognize as defenses define which symptoms we seeas trauma-related. Early conceptions of trauma-related disorders focused on physical signs of distresswhile current ones emphasize mental symptoms, but traumatizing experiences evoke psychobiologicalreactions. An evolutionary perspective presumes that psychophysical reactions to traumatizing eventsevolved to ensure survival. This theoretical review examines several primitive mechanisms (e.g., sensi-tization and dissolution) associated with responses to diverse stressors, from danger to life-threat. Somerapidly acquired symptoms form without conscious awareness because severe stresses can dysregulatemental and physical components within systems ensuring survival. Varied defensive options engage

volutionary biologyvolutionary psychologyainsychoneuroimmunologytress reactions

specialized and enduring psychophysical reactions; this allows for more adaptive responses to diversethreats. Thus, parasympathetically mediated defense states such as freeze or collapse increase trauma-related symptom variability. Comorbidity and symptom variability confuse those expecting mental ratherthan psychophysical responses to trauma, and active (sympathetically mediated flight and fight) ratherthan immobility defenses. Healthcare implications for stress research, clinical practice and diagnosticnosology stem from the broader evolutionary view.

© 2013 Elsevier Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15502. An evolutionary take on trauma and survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1551

2.1. Primitive mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15512.2. Survival systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1552

3. Psychobiological reactions create comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15533.1. The central perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15533.2. The peripheral view . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15543.3. Learning in survival conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1555

4. Varied defenses generate varied symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15564.1. Some disregarded defensive options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15564.2. A continuum of threat imminence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15564.3. The five defense states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15574.4. Summary: Our evolutionary heritage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558

5. Responding to stress entails defense states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15585.1. Defense states are autonomically distinct . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558

5.1.1. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15585.1.2. Freeze-alert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15585.1.3. Flight and fight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1559
5.1.4. Freeze-fright . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.5. Collapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5.2. Defenses sometimes become disorganized . . . . . . . . . . . . . . . . . . . . . . . .

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6. What this means for healthcare researchers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15596.1. Implications for stress research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15606.2. Implications for clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15616.3. Implications for nosology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562

7. Conclusions and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562

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. Introduction

Nothing makes sense in biology except in the light of evolution(Dobzhansky, 1964, p. 449)

The history of trauma-related diagnoses shows that how welassify Posttraumatic Stress Disorder (PTSD) depends on the symp-oms we see and the behaviors we recognize as defenses. Inhe US Civil War, the most closely corresponding diagnosis wasrritable heart (Da Costa, 1871), colloquially called soldier’s heartMackenzie, 1920). During World War I, similar symptoms wereiagnosed as shell shock or the effort syndrome (Lewis, 1940). Withorld War II came the diagnosis of traumatic neurosis (Kardiner,

940). Though the symptoms seen were relatively stable over time,erial diagnoses emphasized differing features. The early medicaliagnoses cued in on somatic complaints, such as exertion, infec-ion, and cardiac or thyroid issues. Yet medical explanations ofhese signs failed to eradicate soldier’s heart. As Wilson (1916,. 120) lamented, “The theorists . . . are bankrupt; the diseaseemains”. When cardiac symptoms came to be seen as signs ofnxiety after World War I, the physical symptoms associated witholdier’s heart were no longer treated as medical problems (Cohn,919).

The term PTSD first appeared as an anxiety disorder in the thirddition of the American Psychiatric Association’s Diagnostic andtatistical Manual of Mental Disorders (DSM) (APA, 1980). We con-inued to group PTSD among the anxiety disorders until the DSM-5APA, 2013). The diagnostic criteria for PTSD still emphasize sym-athetically mediated behavioral responses to traumatic eventsAPA, 2000, 2013). How we see or understand trauma-related disor-ers has research and clinical implications because our perceptionsuide diagnosis, research and treatment. For example, only indi-iduals who complain of mental symptoms are diagnosed withTSD, not those displaying the cardiac signs that would histori-ally have been used to diagnose irritable heart. Some researchersontend that our culture influences trauma responses, while oth-rs stress that our biological survival informs these responses. Bothay be right; but conflicting perspectives such as these could give

ise to differing perceptions of trauma, some of which fail to con-ider exactly what occurs during a traumatizing experience. TheTSD diagnosis highlights reliably observable behaviors. It has pro-ided a focal point for research and has increased the visibilityf trauma-related issues. However, our prevailing notions aboutrauma responses cannot explain the variability that is seen to sur-ound this disorder.

This variability is manifest in two forms: as comorbidity acrossisorders and as varied symptoms that can change over time.he PTSD diagnosis is highly comorbid with other mental healthiagnoses (e.g., anxiety, bipolar disorder, depression, dissociativeisorders, personality disorders, schizophrenia, and substancebuse; Courtois and Gold, 2009; Kessler et al., 2005; Moskowitzt al., 2008). Traumatic events are also surprisingly comorbid withhysical illnesses (Boscarino, 2008; Felitti et al., 1998), with chronic
ain (Lyon et al., 2011), and with some medically unexplainedymptoms (Brown, 2007). In addition, traumatized individualsho receive a diagnosis of PTSD often display widely different
ymptoms, some of which seem unrelated to sympathetic activity

(Lanius et al., 2003; Orr et al., 2004). Symptoms also vary withinpeople over time (Mason et al., 2002; Reinders et al., 2006).

The confusion around both forms of variability has histori-cal roots. Immunology and neuroendocrinology became distinctacademic disciplines because researchers discovered immune andneuroendocrine systems separately. We expect that cognitive andnoncognitive threats will elicit separate central, endocrine, orimmune responses. Ader (1981) coined psychoneuroimmunology(PNI) as a term in the year after publication of the DSM-III; still, thebidirectional communication among psychobiological elementsthat is inherent in PNI has never informed the criteria for PTSD.Comorbid physical disorders surprise us because they violate a pre-sumed independence of distinct reactions to different threats. Yetthe fact that comorbid disorders exist shows that our reactions tocognitive and noncognitive threats are not orthogonal.

Two implicit premises in the prevailing cognitive perspectiveimpede a full understanding of trauma-related symptoms. One isthat mental disorders merit mental explanations. Although men-tal explanations fruitfully address many affective disorders, they donot always fully resolve trauma-related disorders. Generalizing thispremise to trauma-related disorders hinders our understanding ofthe comorbidities observed between traumatic-stress and physicaldiseases. The second premise is that only active defenses count asresponses to trauma. Cannon (1932) contended that we respond tostress with sympathetically mediated actions (i.e., fight or flight).Clinicians and researchers followed his lead by categorizing PTSDas an anxiety disorder (APA, 1980, 2000; Gray and McNaughton,2000). Yet parasympathetically mediated defenses generate symp-toms as well; the variability accompanying these symptoms bafflesus because we do not see immobility responses as defenses, if wenotice them at all. These premises fail to account for the primitivemechanisms seen in trauma-related defensive responses.

In contrast, an evolutionary perspective sees both traumatiz-ing experiences and defensive responses through the longer lens ofbiological survival. Humans inherited the same defensive optionsthat animals use to survive threats such as predation. Bite woundscarry a high incidence of pain and infection. Predation and asso-ciated emergencies, such as infection, require rapid and effectivereactions that take priority over ongoing behaviors. The ability tocoordinate across discrete survival systems should enhance theresponsiveness and effectiveness of behavioral, immune, and neu-roendocrine defenses. Given a shared goal of protecting the host,it would certainly be adaptive for mammalian behavioral defensesto tap into reciprocal communication with the central nervous sys-tem (CNS) and central autonomic network (Maier, 2003). Indeed,this would support immunological memory and learning motivatedby survival demands. Survival-related learning seems to exploitinternal signals of threat, possibly co-opted from older immuno-logic responses to antigens (Ottaviani and Franceschi, 1996). Ourbrain coordinates the neural and physical elements of survival sys-tems, but severe stress disrupts this coordination. Disruptions inthe bidirectional dialogs between the CNS and peripheral signals
may give rise to trauma-related symptoms. Persisting dysregula-tion of primitive mechanisms prolongs symptoms after a dangerhas passed. It follows that trauma-related symptoms are psychobi-ological, and inherently so. They stem from disruptions in primitive

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echanisms, including elements within survival-related systems.n this respect, the symptoms evoked by traumatic-stress differrom behavioral symptoms that do not arise from stress, even whenhey appear similar.

This theoretical review focuses on primitive mechanisms asso-iated with our reactions to diverse threats to survival. Primitiveechanisms contribute to the comorbidity observed among mental

nd physical disorders. Peripherally signaled autonomic participa-ion in the panoply of defensive responses to stress or trauma isxplored as another type of primitive mechanism. Varied defensetates engender varied symptoms that differ both between peo-le and within individuals over time. Thus, primitive reactions toraumatizing experiences potentially lead to symptom variabilitys well as to comorbidity. By taking a broader evolutionary view, weould advance the nosology of stress-related disorders. Nonlinearethods offer promising concepts and analytical tools for under-

tanding the observed variability and will be discussed throughouthe article. It is tough to gauge comorbidity and symptom variabilitysing the prevailing perspective. I discuss why in Sections 3 and 4.

. An evolutionary take on trauma and survival

An early view proposed that the hierarchical organization of theammalian brain evolved to allow newer and more differentiated

eural circuits to regulate the reflexes of ancient regions (MacLean,990). One current view suggests that abstract human cognitivebilities emerge out of negotiations around pre-existing internalvisceral) and external (somatic) constraints imposed by the brain’socation within the physical body (Tucker, 2007). Our brains differrom other mammals more in these newer cortical areas, and less inhe older parts. If survival is threatened, older brain regions reacto external as well as internal threats. Despite clear species dif-erences, the basic defensive options are highly conserved across

ammals. Indeed, birds (Ramirez and Delius, 1979), fish (Smith,992), and insects (Adamo, 2010) show similar responses. It is dif-cult to imagine anything more harshly selected through naturalelection than the adaptations of predators and prey (Barrett, 2005).eactions to infection preceded and likely evolved into behavioralesponses to predators (Ottaviani and Franceschi, 1996). Hughlingsackson’s (1884/1958) concept of dissolution pertains here. Whenevere stress overwhelms our cortical functions, newly unregu-ated primitive brain areas are freed to respond autonomously.he mental, behavioral and physiological reactions to stress thatriginate in these ancient responses integrate poorly with ouronscious experience. Some defensive behaviors are unconsciousBargh and Morsella, 2008) and coordinated outside of humanonscious awareness (Mobbs et al., 2009; Price, 2005). Organismsespond to valid danger signals regardless of their origin. This isecause signals from the periphery convey contextual informationhat aids central processing. For instance, Von Frisch’s Schreckstoff,

pheromone released from the skin, denotes injury when a school-ng fish is bitten (Smith, 1992). Schreckstoff signals conspecifics to

ove away and predators to feed. Simple mechanisms analogouso Schreckstoff may occur in mammals, including humans, as well.

.1. Primitive mechanisms

Sensitization and kindling are two examples of primitive mech-nisms. Sensitization means a progressive amplification of neuralesponses to repeated stimuli. Kindling refers to excitable sensi-ized reactions to repeated stimuli (e.g., as in seizures). Charney
t al. (1993) proposed that sensitization, fear conditioning, andailure of extinction are psychobiological mechanisms involved inTSD. Post and colleagues discussed behavioral sensitization andindling as linked to PTSD symptoms (Post et al., 1995) and the
ioral Reviews 37 (2013) 1549–1566 1551

recurrence of depressive episodes (Post, 2007). Charney et al. sawthat sensitization could explain the heightened responsiveness ofPTSD patients to repeated stressors, and that fear conditioningmight explain the re-experiencing symptoms and compensatoryavoidance or numbing. They proposed that failures of extinctioncould explain the persistence of traumatic memories. Perhaps theseand other primitive mechanisms can expand our ability to describestill other unexplained trauma-related symptoms. An evolutionaryperspective provides a path to find and explore such mechanisms.

In MacLean’s (1990) triune brain, cortical circuits monitor andregulate less differentiated reptilian and limbic areas. In normallearning, for example, processes of sensitization and habituationwork together to spot relevant and ignore irrelevant stimuli. How-ever, sensitization and habituation are associated with granularor pyramidal neural cells in human dorsal and ventral corticol-imbic networks that can become selectively active in contextsthat are safe or threatening (Tucker and Luu, 2012). The corti-cal parts of these two networks lie respectively in the left andright hemispheres. Pribram (2013) notes that left hemisphere nar-rative processes become experienced in the third person, whileright hemisphere processes are experienced in a first-person mode.Our brains reuse existing circuits for new purposes; many humanemotional or cognitive functions are also integrated across the ver-tical hierarchical levels. Physical pain and emotional rejection bothelicit responses in similar brain areas (Kross et al., 2011). Humanempathic concern for others may have evolved out of a capacityto tolerate psychological pain (Tucker et al., 2005). Traumatizingexperiences disrupt the function of, and coordination between, thedual corticolimbic networks. This impairs the effective coordina-tion of survival elements. As psychobiological reactions give rise tosymptoms that are sensitive to stress, our primitive mechanismscontribute to trauma-related disorders in baffling ways. Some PTSDsymptoms reflect a sensitization bias that comes from the humanventral corticolimbic network. Appearing suddenly, these symp-toms are highly specific, persistent, and resist habituation.

The bidirectional communication that is central to psychoneu-roimmunology shows how primitive mechanisms can cross theartificial mental boundaries that divide physical and mental dis-orders. Primitive mechanisms make little sense outside of thisconceptual frame. They are easily overlooked when we forget thatperipheral signals can alter central activity. Survival learning mightengender physical disorders, while mental or emotional issuesarise from psychobiological processes. For example, peptides andother substances serve evolutionarily conserved survival functions.Substance P and its NK1 receptor (Rosenkranz, 2007), ubiquitousthroughout the body, are involved in sensitization and share fea-tures with many common denominators of stress responses inbacteria (Lyon et al., 2011). In PTSD patients, substance P respondsacutely to psychological stressors. It is elevated in disorders sen-sitive to stress, such as sleep disturbance, depression, and severalcomorbidities of physical pain (Geracioti et al., 2006; Lyon et al.,2011). Stam (2007a,b) reviewed neuropeptide Y and other CNS sub-strates implicated with stress sensitization and PTSD in humansand animals. Widespread pain is another expression of a conservedsystem designed to defend or repair the organism following threatsto homeostasis (Lyon et al., 2011). Chronic pain is also associatedwith sensitization. Multiple sensitizing signals in the periphery andwithin the CNS actively generate pain (Woolf and Salter, 2000).Indeed, neuronal plasticity to detect and remember stimuli mayhave evolved to avoid pain (Lyon et al., 2011; Woolf and Salter,2000). Primitive mechanisms, including basic processes of learning,help explain how severe stress could engender physical disorders.
These processes operate outside our awareness, so they might wellescape our notice.
Another example is in order. In numerous publications between1955 and 1996, Garcia and colleagues described examples of

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rimitive learning in survival conditions. Rats normally fed watereceived saccharine and were promptly made ill with radiation.n several studies, these subjects refused saccharine after theyecovered. Taste aversions occurred even when the rats were anes-hetized immediately after drinking the saccharine and were keptnconscious all the way through the radiation sickness (Bermudez-attoni et al., 1988). These highly specific and rapidly acquiredversions are consistent with sensitization, but they contravenehe normal rules of learning. They are difficult to explain in termsf operant or classical conditioning (Garcia et al., 1989). As longs specific criteria are met, Garcia’s surprising and robust find-ngs hold true across various anesthetics and mammalian species,ncluding humans (Garcia, 1990). They imply that peripheral andentral elements work together during survival situations. Moreroadly, and consistent with these results, interoceptive condition-

ng demonstrates that the viscera are able to initiate and conveyome acquired conditioned information (Razran, 1961).

An evolutionary perspective acknowledges bidirectional dia-og in the service of survival. It sees primitive mechanisms as aruitful way to look at PTSD symptoms. Some primitive mecha-isms require bidirectional dialog between peripheral and centrallements. They suffer from stress-related communication break-owns. Others (e.g., dissolution) cause or arise from such failures.he fact that sensitization is seen in chronic pain implies thathared pathways connect comorbid disorders. This, in turn, sug-ests that stress-related physical disorders contain both biologicalnd psychological elements. Primitive mechanisms are broadlynfluential because they are basic and critical. Sensitization pro-esses appear to be involved in the taste aversions of Garcia’s ratsnd in the resistance of symptoms to resolution via cognitive treat-ent approaches for humans with PTSD. Some survival elements

re also highly specific. Garcia’s results imply that a specific prim-tive defense system protects the gut from ingested toxins (Garciat al., 1985). Section 2.2 describes bidirectional processes in sur-ival systems. Because severe stress impairs effective coordinationcross their elements (inflammation, sensitization, etc.), I refer tourvival systems as entangled.

.2. Survival systems

Blalock (2005) and Blalock and Smith (2007) described themmune system as a sensory organ that acts as a sixth sense,dentifying and communicating information about threats not rec-gnized as dangerous by central or peripheral neural systems.urvival situations involve the immune system, and immunenvolvement entails other systems. Our psychological responseso stress trigger inflammatory and neuroendocrine alterations thatan impair physical health (Kendall-Tackett, 2009). Brain-immuneommunications arising from either neurons or immune cellsse cytokines, neuropeptides, and neurotransmitters as signalingolecules (Blalock and Smith, 2007). The ensuing dialog involves

oth parasympathetic (Borovikova et al., 2000) and sympatheticBenarroch, 2009) branches of the autonomic nervous systemANS). By activating the hypothalamic–pituitary–adrenal (HPA)xis and the sympathetic–adrenal–medullary system (Sternberg,006), the brain creates the energy that allows fever to fight

nfection (Maier, 2003). Non-specific behavioral signs, or sicknessehaviors (i.e., altered cognition, depressed mood, disturbed sleep,ethargy), promptly reduce competing energy demands in manypecies (Hart, 1988; Kent et al., 1992). This fits with the idea thaturvival systems coordinate their actions.

Psychobiological elements are entangled across all severity of
tressors. For example, the emotion of disgust actually serves tovoid disease. Stevenson et al. (2012) found that disgust activatesmmune responses and increases body temperature in men. At a
ore mundane level, drowsiness follows a heavy meal and fear

ioral Reviews 37 (2013) 1549–1566

reduces appetite; this is because the energy required for digestionor fear, respectively, limits our available energy for physical activityand eating. Survival systems coordinate behavioral and physiolog-ical elements (i.e., our psychobiological reactions) to best marshallimited metabolic energy in response to diverse threats. Accord-ingly, there is a dose–response association between psychologicalstress and various causes of mortality (Russ et al., 2012). The riskof death increases from cardiovascular events and from suicidesoon after a person learns they have a deadly cancer (Fang et al.,2012). Recurrent traumatizing experiences during childhood canalter how the growing brain develops (Schore, 2003). The behav-ioral defense response that we choose alters the way in which stressdysregulates the HPA (Korte et al., 2005). The strength of entan-gled survival systems lies in their rapid and effective responses. Aweakness is that stress-related disruptions pervade inflammatory,neuroendocrine, and behavioral elements. These entanglementscould impair the function or coordination of components, even-tually disorganizing our defenses.

Infection was a prominent etiological factor in irritable heart(Da Costa, 1871), and occurred in about 80% of the cases withsoldier’s heart (Mackenzie, 1920). Additionally, it was often seenin soldiers diagnosed with effort syndrome (Lewis, 1940). PTSDpatients show autonomic, immune and neuroendocrine alterations(Lewitus and Schwartz, 2009; Pace and Heim, 2011), including epi-genetic changes (Uddin et al., 2010) associated with long-termimmune function. Enhanced inflammation appears to increase therisk of comorbid somatic diseases in women with PTSD fromchildhood abuse (Pace et al., 2012). Current long-term psychologi-cal stress increases glucocorticoid receptor resistance in humans(Cohen et al., 2012). This impairs the down-regulation of pro-inflammatory cytokines and prolongs our inflammation response(Cohen et al., 2012). The phylogenetically ancient co-occurrence ofinflammation and sickness behaviors evolved into psychophysicalparticipation in our trauma responses and trauma-related disor-ders. Indeed, peripheral and central cytokines mediate mammalianhost defenses against infection as they do because the blood–brainbarrier emerged during evolution to protect the brain, thereby dis-rupting communication between phyogenetically older immunecells and preexisting neural control circuits (Maier, 2003). Werarely ask about infection when assessing for PTSD, but perhapswe should.

One more concept needs introducing here. Immune privilege lim-its damage within the brain from peripheral inflammation. Thisprivilege applies only to the parenchyma; information crossesthe blood–brain barrier at the choroid plexus, circumventricu-lar organs, meninges, and ventricles (Galea et al., 2007). Centralcytokines, whether sensitized by the stress of infection or fromemotional trauma, are responsible for sickness behaviors (Dimsdaleand Dantzer, 2007). However, peripheral cytokines induce expres-sion of the same cytokines inside the brain (Dantzer et al., 2008).This allows cellular and molecular images of the peripheral stress orinflammatory responses to form across this barrier (Dantzer et al.,2008). Garcia’s anesthetized rats became suddenly averse to sac-charine in this way. Radiation poisoning created toxins in theirblood that crossed the blood-brain barrier at the area postrema(Garcia, 1990).

From an evolutionary perspective, comorbid nervous and physi-cal disorders occur in a context of incomplete coordination betweenbehavioral and physical defensive elements. Entangled psychobi-ological elements likely respond to all manner of survival threats:internal or external, infection or predation, and social or nonso-cial. Signals from the periphery convey contextual information to
the brain when they coincide with traumatizing experiences, andrepetition strengthens these associations. Yet stress disrupts prim-itive mechanisms as it impairs the bidirectional communicationwithin or across elements of survival systems. Brief disruptions

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ould affect both neural and humoral pathways; prolonged orepeated disruptions set the stage for these components to be dys-egulated. Dysregulation contributes to the connection observedetween traumatizing experiences and various comorbid physical

ssues. This is especially clear for disorders sensitive to stress andor chronic conditions associated with inflammation (Rosenkranz,007), such as chronic pain (Lampe et al., 2003; Lyon et al., 2011)r heart diseases (Boscarino, 2008). Thus, both mental and physicalymptoms invariably characterize all our responses to trauma. Thiseans that disorders sensitive to stress stem from psychobiological

eactions, even if the eliciting stressor is purely psychological.

. Psychobiological reactions create comorbidity

As seen from the cognitive perspective, the brain perceivesnd responds to traumatizing events; peripheral signals, includingomatic sensations such as heart rate, merely reflect the down-tream consequences of central decisions. To those who share thisrevailing view, it follows that our focus should be on the brain, notn the periphery. Yet de-emphasizing physical symptoms in PTSDndercuts the basis for recognizing comorbidities between trauma-izing events and physical disorders. An evolutionary perspectiveccepts that behavioral responses to cognitive stressors share notust common hormones and receptors, but also ancient origins andrimitive functional mechanisms with immunologic responses tontigens (Maier, 2003; Ottaviani and Franceschi, 1996). To fathomomorbidity, we need to employ this broader outlook. The nexthree sections address the process of comorbidity as seen throughn evolutionary lens. I describe relevant bidirectional communica-ions between the brain and the periphery from top-down (Section.1) and bottom-up (Section 3.2) perspectives, and then discussrimitive associations that form as survival is threatened in Section.3. Survival conditions spawn PTSD. Note that some PTSD symp-oms show signs of dysregulation and primitive survival learning.

.1. The central perspective

A purpose of neural activity in response to stress is to selectptimal defenses for survival of the organism. Widely distributedortical areas select defensive strategies; subcortical areas executeesponses (Gray and McNaughton, 2000; Tucker and Luu, 2012).or example, different parts of the midbrain periaqueductal grayPAG) implement active and immobility defenses (Porges, 2011).ust above the brainstem, the hypothalamus prepares the mam-

alian body to carry out a selected defensive response via efferentNS influences on heart rate, blood pressure, and blood distribu-

ion (shifts from the gut and toward leg muscles permit fasterunning). As Garcia’s rats demonstrated, sensitivity to peripheralignals of danger can inform both the perception of and reactionso threats. Indeed, phylogenetically newer cortical regions such ashe right anterior insula, anterior cingulate, and orbitofrontal cor-ex integrate afferent interoceptive feelings from the body (e.g.,utonomic and visceral sensations) to form a sense of self as wells awareness of emotions and sickness behaviors in humans (Craig,002; Critchley, 2005; Dantzer et al., 2008). Exactly how peripheraltress or inflammation affects brain activity is unclear; measur-ng the signaling pathways inside living brain is difficult (Dantzert al., 2008). As cortical regulation of peripheral danger signals ismpaired by stress, those signals become dysregulated. Over time,he defenses themselves may become disorganized.

An evolutionarily older “fast” neural system and a newer system
LeDoux, 1996), both involving the basolateral amygdala (Amaral,003; Davis and Whalen, 2001), respond to danger, threat andncertainty in mammals including humans. The fast system is quiteld. In humans, it initiates unconscious and reflexive defensive
ioral Reviews 37 (2013) 1549–1566 1553

responses (Morris et al., 1999). Bypassing the cortex, this oldersystem includes the right amygdala, thalamus, hypothalamus, andPAG, along with sensory organs (LeDoux, 1996). Cortical and hip-pocampal connections in the newer route allow us to have theexperience of fear. Although cortical connections slow responsetime, they more accurately evaluate sensory information and facil-itate voluntary coping (Hariri et al., 2003; LeDoux, 1996). Data fromanimals corroborate this. Both fast and slow neural systems controlcardiovascular responses via the lateral hypothalamus and prefor-nical region in baboons (Smith et al., 1990). Stimulation of differentportions of the PAG elicits active and immobile defense responses inrats and cats (Bandler et al., 2000). Lateral and dorsolateral areas ofthe PAG are associated with the sympathetic branch of the ANS andwith active defenses in rats (Jansen et al., 1995). Thus, the ventrolat-eral PAG is associated with immobility and the unmyelinated dorsalvagal complex in several mammalian species, including humans(Bandler et al., 2000; Porges, 2011).

LeDoux’s two neural systems convey contextual informa-tion pervasively to cortical areas. Neocortical differentiationadvances from limbic origins. Specifically, two distinct corticolim-bic networks arise from limbic and subcortical areas in humans.They are specialized to respond to differing conditions. Tucker andLuu (2012) contrast a dorsal (mediodorsal frontal) network, activeduring safety and distinguished by impulse and habituation, froma ventral (ventrolateral and orbital frontal) network that accom-modates to novelty and survival pressures. The dorsal networklies primarily in our left hemisphere; the ventral network is dom-inant in our right. These two corticolimbic networks differ in theirevolutionary and ontogenetic origins, as well as neural cells andneurotransmitters. They are specialized for distinct learning andmotivational styles, as Pribram (2013) also notes. Tucker and Luureport that the dorsal network’s pyramidal cells arise limbicallyfrom the hippocampus and anterior cingulate, seeing the worldyou imagine. In contrast, the ventral network’s granular cells, basedlimbically in the extended amygdala and insula, monitor and reactto real world constraints, including various threats. Consolidationof memory also differs; consolidation flows mainly to limbic areasin the ventral network, and from limbic areas in the dorsal net-work. Tucker and Luu suggest that reported characteristics of ourstressful memories might stem from the differing memory con-solidation processes of the two networks. Whereas the intentionaldorsal network handles assimilation learning and spatial or con-figural memory, chaotic or stressful situations engage the ventralnetwork’s sensitization bias and memory for objects or items apartfrom context (Tucker and Luu, 2012). The dual networks normallywork together to enhance complexity and control, as when learningincorporates both habituation and sensitization processes. How-ever, this coordination breaks down under stress. Exactly how eachnetwork responds as danger escalates is not known.

Areas of the ventral network are implicated in mood disor-ders comorbid with stress (Price and Drevets, 2010). Denial (e.g.,anosognosia; Ramachandran, 1995) and impulsive acts of suicidefit with Pribram’s third person mode and hint at the dorsal net-work’s difficulty with unwanted limitations or loss. Aside from thecorticolimbic networks, lower brain regions also respond to trau-matizing experiences. Distinct patterns of brain activation informdifferential behavioral responses as the brainstem, midbrain, andcorticolimbic networks respond to contexts that vary in risk. Cor-tical regions can initiate preemptive strategies such as “tend andbefriend” (Taylor et al., 2000), while the amygdala reacts to presentdanger and the midbrain PAG directs startle responses. In keepingwith dissolution, the more overwhelming a traumatizing experi-
ence is the more primitive the brain areas managing it. It is easyto miss primitive associations that only form under survival con-ditions. To understand these associations, we must appreciate thespecific circumstances that elicit them. A traumatized human might

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ot use the dorsal network that often guides intentional behav-or, because the ventral corticolimbic network takes charge at earlyigns of serious threat. As an inescapable attack becomes imminent,eural activity shifts from overwhelmed cortical areas to brainstemtructures such as the PAG (Lanius et al., 2010; Mobbs et al., 2007).his can affect both memory and awareness in humans. As theentral network detaches from lower brain areas, memory consol-dation in that network is disrupted and the symptoms associated

ith a traumatizing experience would seem anomalous. Measuringust where these shifts occur as threat increases, and how well theyorrespond to human defensive responses or memory issues, is anmportant task for clinical research, although we have lacked thelear yardstick to gauge escalating danger that this would require.

When we have a psychobiological reaction to a stressor, ouronscious awareness of the psychological and biological elementsithin this reaction is often uneven (e.g., as in disgust). We are more

ware of our mental and emotional processes than of the biologicalechanisms that complement them, but stress can limit aware-

ess of any aspect. Specifically, our awareness fails when biologicallements operate outside of consciousness, when stress disruptsrocesses affecting perception or memory, or both. The hierarchi-al organization of the neuraxis becomes selectively relevant in ouraried defensive responses to stress. Severe stress disrupts corticalctivity; it impairs the cortical regulation of lower brain areas andhe monitoring of peripheral signals. Amygdaloidal (not hippocam-al) associations formed during severe stress and unattached toxplicit memories would be more difficult for survivors to integrateith their normal experiences. Anamnestic accounts under-reportnconscious defenses. This limits the value of conjectures fromesearch participants as to their likely responses during hypo-hetical danger scenarios. Although we may be unaware of someiological or mental aspects within our stress reactions, and thusnable to name or differentiate them, they can still influence us.

.2. The peripheral view

One purpose of trauma-related peripheral signals in mammalsay essentially be to call for help. Within the neuraxis, primitive

reas signal danger and thereby activate the corticolimbic networkhat is specialized to respond to possible threat. Garcia proposeddding a feedback (FB) term to differentiate the cognitive (CS-US)rom motivational (US-FB) aspects of conditioning, thus changingavlov’s CS-US to CS-US-FB (Garcia, 1990). His US-FB pathway,ilent when the dorsal corticolimbic network is dominant, sig-als unconscious homeostatic evaluative data to overrule previousS-US associations as the ventral network engages in stress. Theeriphery can denote a dangerous or life-threatening event thatequires central attention, as Schreckstoff and Garcia’s results con-rm. The body (here, the gut) signals a dangerous context if nausea

ollows the taste of a new food, even while asleep. The human ven-ral corticolimbic network is cytoarchitecturally primed to monitoreripheral feedback (Tucker and Luu, 2012).

Data suggest that gut microbes can alter functioning botheripherally, in the enteric nervous system, and centrally, in therain, thus affecting behavior in both mice and humans (Bravo et al.,011; Forsythe et al., 2010). Peripheral feedback might follow sev-ral internal pathways. Both humoral (cytokine) reactions to stressr infection, and neural signals from the gut or elsewhere in theeriphery, can induce central changes (e.g., altered firing rates)esigned to regulate peripheral responses (Blalock, 2005). Theagus nerve, with far more afferent than efferent fibers (Agostonit al., 1957), is suited to relaying visceral chemosensory signals to
entral autonomic network nuclei in the mammalian CNS (Bravot al., 2011; Goehler et al., 2000). A third internal path might aug-ent the neural and humoral routes. Extracellular electric fieldseasured in rat cortical tissue increase the synchronicity of neural
ioral Reviews 37 (2013) 1549–1566

firing, with neural responsiveness most sensitive to field oscilla-tions of <8 Hz (Anastassiou et al., 2011). These fields represent adirect route for the brain to monitor peripherally signaled auto-nomic activation associated with defense states. Visceral signalsthat denote contexts of danger or life-threat, sensed continuouslyvia heart rate by extracellular fields within the cortex, would informcentral processes of defensive needs. Thus, these signals could biascognitive operations without our awareness. Consider how sensi-tively our brains alter autonomic activity in response to contextsthat we experience as dangerous or life threatening.

The brain selects viable defensive options based on the char-acteristics of each threat. In environments perceived as safe,people normally respond to others via a social engagement systemmediated by the ventral vagus (Porges, 2011). Environments expe-rienced as unsafe evoke an adaptive range of preparatory defenses,mediated sympathetically or dorsal vagally (Porges, 2011). Visceralsignals that portend danger or occur in a context of life-threat canalter the subjective perceptions of ambiguous stimuli. For example,physical changes occur in the middle ear when someone does notfeel safe. These changes lessen acuity to mid-range (human vocal)frequencies in exchange for adaptively heightened sensitivity toboth low and very high-pitched sounds (Porges, 2011). Olfactorysignals in the sweat of frightened men bias women to interpretambiguous facial expressions as more fearful (Zhou and Chen,2009). Thus, context (specifically, perceived safety or its absence)alters responses to indeterminate stimuli: it constrains options(e.g., which of two forms of learning pertain). Dreams provide athird example. In REM sleep, dreams mitigate the negative affec-tive charge of disturbing experiences, because REM sleep normallysuppresses adrenaline and amygdaloid activity (van der Helm et al.,2011). In contrast, REM sleep nightmares in PTSD occur in a milieuof high adrenergic and amygdaloid activation and repeatedly fail toreduce emotional charge (Walker, 2009). Why normal suppressionfails in PTSD is unknown (Walker, 2009), but persistent feedbackof danger from the periphery or brainstem might countervail nor-mal suppression. Indeed, consolidation of fear extinction memoryrequires brainstem pontine wave activity during REM sleep in rats(Datta and O’Malley, 2013). Each of these examples illustrates howa signal of danger or safety that comes from the periphery or aprimitive brain area can alter central processing in humans.

The parasympathetic nervous system is involved in regulatingthe HPA axis through two branches of the vagus nerve (Porges,2011). Specifically, ventral vagal dominance is associated withsocial engagement in safety. Ventral vagal withdrawal opens thedoor for sympathetic dominance (Porges, 2011). As the ventralvagus withdraws, sympathetic activity fuels active behavioralresponses to escapable or controllable dangers. However, an activedefense seldom makes for a viable response to inescapable oruncontrollable threats (e.g., life-threat). When life-threat occurs,dorsal vagal engagement instills immobility (Porges, 2011). (Notethat the ventral corticolimbic network and dorsal vagus respondto threats; the dorsal corticolimbic network and ventral vagus mayengage during safety.) Consistent with entangled survival systems,varied defensive behavioral options inform immune responses toantigens. Thus, catecholamines are preferentially associated withactive defenses while increased cortisol reflects engagement in acontext of uncertainty and threat (Henry, 1992). Decreased cortisolin humans marks a reduced threat (Dickerson and Kemeny, 2004)that could follow subsequent disengagement (Mason et al., 2001).In addition, we rarely consider that gut microbes in mammalsincluding humans detect and respond to catecholamines, hencealtering susceptibility to infection under stress (Freestone et al.,
2007).
Greater attention to specific behavioral defensive responses candeepen awareness of our psychobiological reactions to stress. Inthe past, anxious stress was thought to impair immune responses

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Kiecolt-Glaser et al., 1998), but now specific defenses appeareterminative (Korte et al., 2005). Responses to acute stress facil-

tate wound healing, while responses to chronic stress impedeecovery (Dhabhar, 2009). Hence, defense states may provide theffective yardstick for calibrating these shifting central and periph-ral responses to stress that we need. Acknowledging peripheralarticipation invites us to consider how the brain responds if araumatized periphery continues to signal threat after a danger hasassed. Recall that severe stress inhibits LeDoux’s slow neural sys-em and the dorsal corticolimbic network. Primitive brain areasre apt to respond crudely when buffeted by peripheral feedbackust as their normal regulation from cortical regions goes offline.fter recovery, Garcia’s rats appeared surprised by their newfoundisgust of saccharine (Garcia, 1990). We may also form associa-ions in survival situations that later we cannot recall having made.isrupted cortical regulation during severe stress is selectivelyssociated with certain defensive responses in humans and otherammals. Along with survival systems and primitive mechanisms,

issolution plays a role in survival learning.

.3. Learning in survival conditions

The human brain’s vertically organized hierarchical systems areulnerable to dissolution in survival situations. Disrupted corticalegulation of primitive areas could allow an uncoupling or over-oupling of behavioral and autonomic responses. This can occurermanently following lesions in the orbitofrontal cortex (in mar-osets; Reekie et al., 2008) or temporarily in stress via dissolution.ith severe stress, peripheral signals become unregulated. Addi-

ional information comes from work with spinally transected rats,hose spinal cords are severed from the brain at T2. The spinal

ord uses sensitization or habituation to process pain, dependingn its controllability (Baumbauer et al., 2009). An experience ofncontrollable shock, physical injury, or inflammation as a neonateas long-term consequences for these paralyzed rats, reducing the

earning capacity of their spinal circuits for months. Young et al.2008) report that immune and inflammatory responses (i.e., sen-itization) to such neonatal experiences increase the survival ofpinal cells in these rats, while altering their pain reactivity andain processing into adulthood. Their findings show that simple

earning processes both occur and become dysregulated below therainstem (cf. Bykov, 1957; Razran, 1961). Sensitization impairsabituation in these rats because a release of substance P and itsK1 receptors floods multiple segments of the spinal cord, where itinders the ability to form specific associations (Baumbauer et al.,009).

How can it be adaptive to impair the ability to learn? Sharedechanisms explain how sensitization inhibits subsequent plastic-

ty in the spinal cord (Baumbauer et al., 2009). This is a characteristicf entangled systems. Other anomalous yet patently adaptive sur-ival systems involve limbic (emotion) areas such as the amygdalaGarcia, 1990; Garcia et al., 1985), and the fact that the vaguserve maintains some of these enduring associations (Kiefer et al.,981) implicates cholinergic involvement and certain defenses.onditioning normally requires brief inter-stimulus intervals, andonditioned stimuli seldom provoke disgust or fear (Garcia et al.,984). In contrast, primitive associations can form despite very long

nter-stimulus intervals (Garcia, 1990). The specialized US-FB asso-iations processed by the ventral corticolimbic network in stressiffer from the CS-US associations of the dorsal network in safety.abituation and sensitization, immune activation with disgust, and

ickness behaviors are all examples of entangled survival systems.
Data available since the inception of the PTSD diagnosis
ink psychoneuroimmunological processes with trauma-relatedisorders. Bidirectional communication supports insights notpparent using either the physical explanations of irritable heart

ioral Reviews 37 (2013) 1549–1566 1555

or the cognitive explanations of PTSD. During severe stress (i.e.,a life-threat), peripheral signals can become uncoupled from thecorticolimbic networks that normally guide responses and formour conscious awareness (Mobbs et al., 2009; Tucker and Luu,2012). Dissolution implies dysregulation. Primitive associationsform rapidly and easily, but only in survival conditions; they areoften highly specific. For instance, although food aversions occurefficiently when nausea follows a novel taste (Bermudez-Rattoniet al., 1988), nausea does not teach rats to avoid the locationwhere they encountered a poison or the radiation (Garcia et al.,1984). Taste may cause illness. A specialized gut-defense systemuses taste and odor to avoid ingesting toxins (Garcia et al., 1985).Vibrations might cause pain. A primitive skin-defense system thatis reminiscent of Schreckstoff in vertebrates selectively associatesexternal stimuli with predatory attack (e.g., foot shock; Garciaet al., 1985). Species-specific defense reactions in animals (Bolles,1970; Brown and Chivers, 2005) and specialized preparednesslearning in humans (Cosmides, 1989; Ohman and Mineka, 2001)illustrate the value of biologically restricted response tendenciesshaped by survival-related evolutionary pressures. The symp-toms of PTSD reflect their shared source: In dire circumstances,immediate needs trump and curtail subsequent abilities.

How we see PTSD can make these symptoms confusing for PTSDsufferers as well as clinicians and researchers. For example, suffer-ers of PTSD lack a context to understand their intrusive symptoms.Knowing that their intense reactions are disproportionate adds totheir distress. Frustrated by the inability to control their uncon-scious reactions, some even fear going insane. Researchers andclinicians who think of PTSD as a mental disorder rarely considerthat symptoms of hypervigilance might stem from sensitization,since this view is not conducive to recognizing primitive mech-anisms. Yet, the presence of a form of sensitization in the spinalcords of spinally transected rats, and its long-term reciprocal effectson habituation, support the idea that primitive mechanisms associ-ated with trauma-related disorders can occur below the brainstem.The hypervigilance and intrusive symptoms of PTSD reflect sensi-tization because that is how our corticolimbic networks negotiatethreat. By inhibiting habituation, unregulated sensitization mayprolong PTSD as well as other disorders.

Primitive mechanisms operate in survival conditions with inter-mittent cortical regulation. They offer a basis for understandingcomorbidity and the characteristics of trauma-related symptoms.Yet the specialized associations in survival learning are oftenunseen (Bolles, 1970). Garcia, who studied taste and other aversionsdecades before the PTSD diagnosis, did not mention implicationsrelated to trauma. He noted two practical applications for his dis-coveries. Wolves fed poisoned mutton rarely kill the sheep oneastern Washington ranches, and children with cancer who receivea novel candy just before each chemotherapy treatment couldcontinue to enjoy their preferred foods (Garcia, 1990). He neverexplicitly described these aversions as psychobiological reactionsin the service of survival. Silove (1998) later implicated ancientand primitive learning mechanisms in the formation of intrusivePTSD symptoms, but cited neither Garcia’s work nor interoceptiveconditioning as exemplars. Parallels between the hypervigilancesymptoms in PTSD and sensitization in pain have also gone unrec-ognized. Fragmentation and isolation often mark trauma-relatedissues. The fact that psychobiological mechanisms respond tothreat captures a critical but neglected consequence of survival-related traumatic-stress. Outside of this context, variable responsesto stress or trauma seem anomalous. They confound the pre-vailing view. By accepting that there are phylogenetic influences
over stress responses, researchers can better identify them. Thiscould advance efforts to treat trauma-related disorders. As willsoon become clear, unseen responses to trauma create inexplicablesymptom variability.

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Extensive symptom variability presents a puzzle similar toovariation across disparate diagnoses. The prevailing view doesot predict either of these manifestations of variance. It can-ot explain the varied symptoms that we see, because it expectsraumatizing experiences to evoke active defenses. The diagnosticriteria for PTSD still derive from Cannon (1932), who emphasizedympathetically mediated active responses to threats. Followingis lead, we labeled PTSD as an anxiety disorder. Cannon min-

mized any defensive role for a parasympathetic system that heaw as focused on rest and recuperation. To those sharing this pre-ailing view, it follows that we should focus on active responses,hich means fight and flight. Yet this activist premise does not sayhat happens when no active defense is viable. The reality of dor-

al vagal immobility defenses refutes this view. Together, activend immobility defense states generate varied symptoms as theyhift, not just across different people, but also within the samendividual over time. An evolutionary view embraces the immo-ility options that evolved prior to mammalian active defensesPorges, 2011). Sections 4.1–4.3 describe the panoply of ourehavioral defensive options within a changing context of threat

mminence.

.1. Some disregarded defensive options

Pervasive physiological variability arises from differing riskperceptions,” behavioral defense “choices,” and autonomic rolesi.e., parasympathetic/sympathetic regulation; Korte et al., 2005).nfortunately, the literature on human stress responses only inter-ittently acknowledges the full range of defensive options. Various

nfluential accounts (e.g., Bolles, 1970; Gray and McNaughton,000) focus on sympathetically mediated active defenses and dor-al PAG, overlooking the ventrolateral PAG and its more primitiveorsal vagal (immobility) defenses. Hence, the prevailing viewelectively disregards autonomically mediated states that evolvedo respond to life-threat, which is the most severe category of stress.he minimization of parasympathetic contributions to defensiveptions, and our failure to distinguish dorsal vagal from ventralagal influences, have led us to under-appreciate several immobil-ty defenses.

In 1870, Paul Bert discovered bradycardia in ducks (Butler andones, 1982) while inadvertently provoking a state of collapse.ccording to Campbell et al. (1997, p. 55), Bert “forcibly held auck’s head underwater and measured heart rate by feeling theulsations of the heart through the breast. Submersion produced

sustained decrease in heart rate that persisted until the headas lifted and breathing resumed.” Researchers studying the diving

eflex assumed that voluntary dives produced cardiovascular andetabolic changes similar to those that occur during forced div-

ng. A century later, telemetered crocodiles in a laboratory revealedramatic bradycardia when researchers triggered their dives, inontrast to their heart rates during voluntary, undisturbed divesGaunt and Gans, 1969). This is how withdrawal (fear) bradycardiaas distinguished from diving bradycardia. Fear-related bradycar-ia is a salient characteristic of collapse, the defense state thatrimarily responds to overwhelming threat. Yet this form of brady-ardia is rarely noticed.

In 1942, Cannon investigated the “Voodoo” death phenomenon.iewing defenses as sympathetically mediated, Cannon supposeduch deaths would stem from the shock of too much adrenaline:persistent excessive activity of the sympathico-adrenal system”
Cannon, 1942, p. 174). In fact, deaths were caused by parasym-athetic over-activity (i.e., collapse). Richter (1957) found thatild rats forced to swim showed decreased respiration and body
emperature, and eventually succumbed with the heart in diastole.

ioral Reviews 37 (2013) 1549–1566

Later, Hofer (1970) reported very low heart rate, cardiac arrhyth-mias, and increased respiration during prolonged immobility infour species of recently caught wild rodents exposed to predatorsin an open area with no ability to escape. This was not long aftertelemetry data led to our awareness of fear bradycardia (Gauntand Gans, 1969). Thus, physiological measures consistent withcollapse corroborate Richter’s results.

The idea that trauma-related disorders involve defensiveresponses is not new. Rivers (1920) described five “danger-instincts” seen in military survivors of World War I combat: flight,aggression, immobility, and collapse, plus “manipulative activity”meant to avoid, escape, or overcome a threat. However, historicaland nosological considerations have coalesced against explicitlyincorporating defense states within criteria for trauma-relateddisorders in the DSM (APA, 1980, 2000, 2013). As a result, trauma-related diagnoses exclude some defense states. There is no coherentrationale for the exclusion. Sporadic efforts to associate theseprimitive mechanisms with trauma responses have either beenincomplete, in that they focused only on sympathetically mediatedresponses, or unheeded.

Immobility defenses are easy to miss. In addition, theseresponses to life-threat implicitly remind us of our mortality.Humans react to deeply threatening facts, including remindersof death (Arndt and Vess, 2008; Pyszczynski et al., 1999), withdenial. This might contribute to our neglect of immobility defenses.Denial could also be implicated in the “episodic amnesia” (Herman,1992b) that historically has marked the traumatic-stress field. Inorder to appreciate fully the dynamics of defense state involve-ment across trauma-related disorders, it is necessary to see howthreat detection, threat appraisal, and defensive options relate tothreat imminence.

4.2. A continuum of threat imminence

Mammalian defensive responses take priority over other behav-iors under conditions of threat (Fanselow and Lester, 1988).Predatory imminence refers to a continuum of perceived dangerfrom predation. This continuum ranges from minimal perceivedthreat, to predator detection, then predator contact, and escapeor death (Fanselow and Lester, 1988). Defenses against preda-tion could have been co-opted to respond to a variety of extremesituations – including abuse, combat, car accidents, and moderndisasters. This represents a special case of threat imminence, rele-vant through exaptation (Gould, 1991) to a wide range of traumaticrisks. Gould and Vrba (1982, p. 4) first proposed the term exapta-tion to name “features that now enhance fitness but were not builtby natural selection for their current role,” distinguishing it fromadaptation, or those features built by selection for their presentrole. Adaptation facilitates incremental evolutionary linear change;by contrast, exaptation reveals the quirky diversity and unpre-dictability (Gould, 1991) that is characteristic of nonlinear changein complex systems.

Most easily characterized in terms of physical distance, preda-tory imminence is far more subtle. Fanselow and Lester (1988)noted that an approaching predator looking toward its prey ismuch more dangerous than one looking away or moving at a tan-gent. Illness or injuries, as well as specific predator characteristics,influence attack vulnerability and thus threat appraisal. Threatimminence is similarly nuanced and subjective. Appraisals of pre-dation or threat shared a subjective element with Criterion A inAcute Stress Disorder (ASD) and in PTSD (e.g., APA, 2000; Fanselowand Lester, 1988; Mobbs et al., 2007). The DSM-5 removed emo-
tional reactions from Criterion A (APA, 2013), but they still occur.Lang et al. (1997) introduced the phrase defense cascade to frame thespace across which defensive options unfold as threat imminencerises. Defenses begin with the orienting response toward a novel

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hreatening stimulus (Graham, 1979; Graham and Clifton, 1966;ila et al., 2003). What happens next depends on the context.

In environments perceived as safe, orienting and motionless-ess habituate rapidly. When something changes in such annvironment, we resume our activities after a quick glance toake sure this change is not a threat. Orienting to novelty and

abituating to prior concerns signifies healthy adaptation in safenvironments (Thayer and Friedman, 2002). In a more sketchyetting, detection of novelty signals a need to accommodate to aotential threat by selecting from mutually incompatible defen-ive responses. Gray’s behavioral inhibition system thrives inuch settings, where novelty instantiates an approach–avoidanceonflict (Gray and McNaughton, 2000). Defensive responses associ-ted with behavioral inhibition habituate slowly (Sánchez-Navarrot al., 2006; Sokolov and Cacioppo, 1997) and prolong stilling. Notehat the shift from orienting to defensive responses with a grow-ng risk (e.g., appraising a non-startling stimulus; Graham, 1979)ntails a transition from internal intentions to reactive attentionr vigilance, befitting a shift to the ventral corticolimbic network.onlinear changes in heart rate (Sánchez-Navarro et al., 2006)ttend a concomitant interplay of parasympathetic ventral vagalnd sympathetic influences. Such changes are well suited to non-inear analyses (Lafitte et al., 2006).

Together, threat imminence and the defense cascade highlightmportant contextual contributions to the full range of defense-tate variability. Evolutionary views of trauma-related disordersre congruent with comparative and ethological approaches andith embodied psychophysiology research (Critchley, 2005; Dixon,

998; Gilbert, 2001; Tinbergen, 1974). Investigators employ-ng these approaches routinely observe unconscious indicationsf defense state activation (e.g., heart rate, muscle tension) inesponse to stress. Clinicians working with traumatized patientslso notice the pertinence of unconscious somatic signs. In con-rast, others develop a different understanding. When clinicians oresearchers ignore peripheral feedback signals that only respondo threats, they miss nothing as long as their procedures are non-hreatening and do not elicit stress responses. However, thoseocused on central activation (or CS-US associations) might reads superfluous the influence of somatic activation (US-FB) affect-ng brain activity. From the perspective of someone inattentive totress, an inoffensive immobility defense (devoid of sympatheticctivation) could appear as a tranquil brain. This is partly a mat-er of selective experience, although a left hemisphere engaged inolving problems does not sense danger or notice issues beyondhose deemed relevant (McGilchrist, 2009).

In any case, an early hint of potential danger poses a problemequiring a prompt response. Choices need to weigh the benefitsf deflecting or inhibiting a potential attack in advance (e.g., byeeking support), or finding ways to approach, withdraw, or hiderom a present threat (Marks, 1987). Some defenses, such as anal-esia or nurturance, begin before they are needed. Analgesia is ahysiological adjustment that prepares for possible injury withoutompromising other defenses (Bolles and Fanselow, 1980). Deflect-ng or inhibiting attack (Marks, 1987) in the absence of immediateanger could avert a future attack. This mammalian strategy is akino the preemptive “tend and befriend” responses that Taylor et al.2000) attribute to human females. Yet diverse nurturing behaviorsromote safety and reduce distress in both sexes and in a variety ofpecies (Geary and Flinn, 2002; Gilbert, 1995; Marks, 1987). Clearly,he value of each defensive option varies with one’s position along

continuum of threat.

.3. The five defense states

Five defense states emerge, unbidden, when danger is present:reeze-alert, flight, fight, freeze-fright, and collapse, in order of

ioral Reviews 37 (2013) 1549–1566 1557

increasing threat imminence. On sensing an unfamiliar stimulus(or before venturing outside), orienting is the best option: “Is itsafe?” Freezing (i.e., alarm; alert immobility) is a common, adap-tive initial response at post-encounter, when the predator is firstdetected but has not yet seen its prey. Movement attracts atten-tion. Freeze-alert buys time for appraisal while minimizing the riskof detection. Fleeing would tempt the predator to take pursuit. Ifa predator does not notice movement, they might lose sight of theprey or lose interest – another sound or movement could distractthem (Suarez and Gallup, 1981). If the danger escalates to a level ofimminent threat, dramatic changes occur as the predator preparesto strike. An active defense (flight, then fight) may emerge here,so long as a subjective appraisal suggests that conditions warrantsuch actions (Blanchard et al., 2001; Shuhama et al., 2008).

Bracha (2004) identified two variants of the freeze response,here termed freeze-alert and freeze-fright. Some publishedaccounts of “freeze” describe freeze-alert, some freeze-fright, andothers blur this distinction. Like the Indian tale of a group of peoplefeeling different parts of the same elephant in a dark room, con-fusion arises over terminology because authors presume differentunnamed variants. It is important to distinguish freeze-alert fromfreeze-fright because these are distinct autonomic states, respon-ding to differing degrees of appraised threat. Freeze-alert definesan initial and often brief interruption of ongoing activities whileappraising early indications of potential danger; it extends the still-ness of orienting. Freeze-fright occurs as circa-strike approaches orin a context of perceived inescapable threat (e.g., entrapment orlife-threat) where it can persist until the threat ends. The freeze-fright state binds immobility with a readiness to act. Paralyzing fearand tonic physical immobility characterize this latter freeze vari-ant, sometimes described as scared stiff (Blanchard and Blanchard,1969; Marx et al., 2008). Both freeze variants predominate beforecontact, freeze-alert before and freeze-fright after the predatordetects its prey. Both are preferred over flight even when knownescape routes are available (Fanselow and Lester, 1988).

Collapse (feigning death) emerges with an overwhelming attackif active defenses are not viable (Bandler et al., 2000; Porges,2011). A simple thought experiment illustrates these five defen-sive options. Imagine that you surprise a large bear while alone inthe wilderness. Your immediate stillness is the freeze-alert state.If the bear moves off, you can return home with an exciting storyfor your family. If the bear approaches, your danger deepens. Nei-ther flight nor fight offers a viable option in this and many othercases of extreme threat, where active defenses increase the risk ofdeath. The best option here is freeze-fright, although your chancesare slim unless a hunter is nearby. Finally, when the bear has youin its mouth, you are out of options. You go limp in a state ofcollapse, as described by Livingstone (1857) and others (Levine,2010). Collapse reduces the likelihood of continued violence, whilepreparing the individual for injury or death (release of endogenousopioids decreases pain; Bolles and Fanselow, 1980). Immobility isthe most effective response during attack because quiescence elim-inates auditory and visual cues that elicit or maintain aggression.All of these defense states survive in us from our evolutionary pastbecause each has enhanced the odds of survival.

Hence, the behavioral defensive options are two active andthree immobile states. Viewed through a fuzzy lens, the fivedefensive options appear as two: active and immobile (or pas-sive) (Herman, 1992a; Lanius et al., 2010; Terr, 1991), oftencorresponding to, and confused with, acute vs. chronic stressors.Knowledge of defensive options allows a reconsideration of thepreviously mentioned research on connections between immune
function and stress responses. For example, Rosenberger et al.(2009) attribute differential healing after knee surgery to varieddefensive responses that alter the distribution of immune cells inblood. In their view, short-term stress facilitates wound healing

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hile chronic stress slows the speed of recovery (Dhabhar, 2009;osenberger et al., 2009). Note that these stressors entail activesympathetic) or immobility (dorsal vagal) defenses, respectively.ecognizing how these distinct defense states affect catecholaminend glucocorticoid patterns could enhance our understanding ofhe contradictory immune alterations reported across samples ofTSD patients (Pace and Heim, 2011). Identifying not just the activeefenses but also all three immobility states in comparative studiesight clarify confusion over immune and stress interactions across

hyla (Adamo, 2010).Distinguishing each defense state provides a more accurate pic-

ure of the varied responses elicited by differing stressful contexts,aking it possible to see through a sharper lens. When defense

tates unfold as danger escalates, they calibrate the defense cas-ade. This allows us to link subcortical, limbic and cortical activityo peripheral responses across the threat imminence continuum.istinguishing the three superficially similar but autonomicallyistinct immobility defenses yields particularly valuable informa-ion. If we limit threat to discrete points (e.g., post-encounter andirca-strike; Mobbs et al., 2009), we neglect some shifts in defen-ive responses as stress becomes life-threat. Recognizing that therere five defense states should help researchers clarify reported age,ehavioral, immune, neuroendocrine, sex, and species differences

n response to stressful experiences. This could also improve treat-ent outcomes.

.4. Summary: Our evolutionary heritage

An evolutionary view sees that humans inherited ancientsychophysical responses to aid in the service of our survival.pecialized primitive mechanisms serve as elements within imper-ectly coordinated survival systems. Phylogenesis and evolutionaryonstraints gave rise to bidirectional dialog among central anderipheral elements responding to diverse threats. Disruption ofhese elements during stress creates some puzzling symptoms that

ay give rise to comorbid physical disorders. In survival situations,issolution and sensitization operate outside our conscious aware-ess and can alter our cognition. Differing defensive options aressociated with certain midbrain and limbic regions as well as withhe corticolimbic networks. Active defenses require cortical activa-ion in support of strategy or tactics, while collapse does not (Llinás,001; Mobbs et al., 2007). The insight that trauma-related symp-oms are inherently psychobiological expands our perspective onrauma-related disorders. It invites us to consider the involvementf both central and peripheral elements.

The classical conception of the autonomic nervous system pre-umes a sympathetic branch that is responsive to stress, pairedgainst one parasympathetic branch that is not. This schemexcludes some primitive defense states. In so doing, it minimizesrauma disorders much as Saul Steinberg’s New Yorker cover, “Viewf the World from Ninth Avenue,” diminished everything west ofhe Hudson River. Because influential textbooks reiterate this sym-athetic bias (e.g., Andreassi, 2007, pp. 64–67), they hinder a widerecognition of vagally mediated immobility defenses and relatedhenomena such as autonomic dysregulation or dissociation. Inddition, the sole English word for “freeze” fails to distinguish twoutonomically distinct freeze states. Conflating these states, in turn,bscures important characteristics of all three immobility defenses.ccordingly, popular (e.g., media) attention emphasizes sympa-

hetically mediated defenses such as “fight and flight”. Too often,esearch and clinical efforts do so as well.

Safety and threat denote fundamental contexts. They organize
volutionarily adaptive behaviors (Gilbert, 1993; Porges, 2011).ive autonomically distinct mammalian defense states are medi-ted by two types of parasympathetic activation (i.e., ventral vagalnd dorsal vagal), as well as by sympathetic activity. Humans
ioral Reviews 37 (2013) 1549–1566

inherited this panoply of mammalian defenses; any of these statescan emerge when stressful experiences exceed our ability tocope. These varied defense states generate the diverse symptomsreported in the traumatic-stress literature. Thus, an evolution-ary view resolves some confusion about trauma-related disorders.Applying current knowledge of phylogeny and psychoneuroim-munology will allow scientists and clinicians to further advancethe traumatic-stress field. Section 5 details the primitive autonomicpatterns associated with specific defense states. Section 6 exploressome implications for healthcare.

5. Responding to stress entails defense states

The five defenses – freeze-alert, flight, fight, freeze-fright, andcollapse (Bracha, 2004) – are distinct autonomic states. Physio-logical preparation for flight differs from that for fighting. Thethree immobility options (both freeze states plus collapse) involveunique patterns of autonomic activation in the service of distinctgoals. Dimensions of emotionality and coping style appear inde-pendent (Koolhaas et al., 2007). Emotions, such as anger and fear,are not exclusively associated with distinct forms of autonomicactivity (Barrett, 2006). Measurement errors surrounding primaryand secondary emotions further confuse the issue. Typically, angeris associated with fight and fear or panic with flight, but individ-uals can fight when afraid, run when angry, and be immobilizedwhen experiencing numbness, anger, or fear. Defenses might ormight not involve intense emotions or even awareness; still, thefamiliarity of emotions and their perceptual salience distracts ourattention from any concomitant psychobiology. Numerous anec-dotal accounts document the successful use of various active andimmobility defenses by survivors of animal attacks, senseless vio-lence, or other traumatizing experiences. Their shifting responsesto these threats directly engage dynamically changing autonomicactivations. Defense states are the building blocks of this variance.Understanding these primitive states sheds light on our psychobi-ological reactions to stress and trauma.

5.1. Defense states are autonomically distinct

The autonomic characteristics that define each defense state aredescribed below, in order of increasing threat imminence. Note thatthe two active defenses typically respond to variations in appraisedescapable danger; freeze-fright and collapse respond to varieduncontrollable threats. Ventral vagal dominance during safety con-trasts with its absence in all defense states. Descriptions begin witha normal state of safeness, reflecting its importance.

5.1.1. SafetyThe experience of safeness promotes parasympathetic ventral

vagal dominance. People ideally conduct activities of daily livingin this state. In safe environments, ventral vagal activation facil-itates social engagement and counteracts unwanted sympatheticarousal (Porges, 2011). Known as the vagal brake, strong ventralvagal activity slows heart rate below the intrinsic rate of the sino-atrial node as we actively engage challenging situations (Porges,2011). Measures of ventral vagal activity (e.g., heart rate variabil-ity, or mutual gaze) reflect resilience, and can gauge how readilysocial support or psychotherapy alleviates stress in patients. Selye’seustress implies that we can maintain ventral vagal dominance aswe cope with challenges.

5.1.2. Freeze-alertA shift to the freeze-alert defense state occurs when a threat first

exceeds our ability to cope. We relinquish parasympathetic controlof breathing as ventral vagal withdrawal lifts the vagal brake; the

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diom “bated breath” names the familiar side effect of this involun-ary transition to wariness and unfettered sympathetic dominance.eart rate quickens abruptly in preparation for active defenses.reeze-alert provides space to assess the nature and degree of anyotential threat. It affords time to select among active or immo-ility options. Sympathetic activity increases the heart rate furthertachycardia) if this state is prolonged. Extended freeze-alert poten-iates startle in rats (Leaton and Borszcz, 1985). If movement isalled for, it is explosive, “as if the freezing animal is tensed upnd ready to explode into action if the freezing response fails it”Fanselow and Lester, 1988, p. 202). Note that the cardiac symp-oms typical of irritable heart (Lewis, 1940) imply an extendedreeze-alert state.

.1.3. Flight and fightSympathetic activity mediates both flight and fight. Active

efenses, being autonomically interchangeable, can switch fluidlys needed. The differences between these two states involve bloodow (i.e., toward the legs in flight, or to the arms and jaw for fight),

acilitating appropriate movements in response to each threat. Asentioned previously, flight or fight is sometimes ill advised. Active

efenses epitomize the fundamental motivational systems of with-rawal and approach (Schneirla, 1959).

.1.4. Freeze-frightFreeze-fright bespeaks constraint or indecision around the use

r timing of active defenses in circumstances already appraiseds dire. Pending an active response, coactive (simultaneous) sym-athetic with parasympathetic dorsal vagal activity engages thereeze-fright defense state (Henry, 1992; Koizumi et al., 1982;hang et al., 2004). Individuals in either freeze state appear as ton-cally immobile, tense, and primed for movement. Dorsal vagalctivity distinguishes freeze-fright from freeze-alert. It inhibitsovement, including startle, and may rouse a sense of being unable

o move. As Davis and Astrachan (1978) have noted, “at leastwo processes that have opposite effects on startle must operates fear increases” (p. 102). Freeze-fright is often accompanied byear (Fiszman et al., 2008; Fusé et al., 2007; Leach, 2004; Marxt al., 2008). Coactive sympathetic and dorsal vagal activationtrengthens heart contractions, increasing blood flow while slightlyecreasing heart rate relative to flight or fight (Brooks and Lange,982; Koizumi et al., 1982). This is why our hearts pound after arightening dream. Simulated physical attack (Mobbs et al., 2007)an induce this state in humans.

.1.5. CollapseFinally, the hypometabolic defense state of collapse emerges

hen all other options, whether tried or not, have become futile. Inumans, inhaling carbon dioxide under experimental conditionsan induce this state (Wetherell et al., 2006). With extreme threati.e., inescapable or life-threat), sympathetic activity recedess the autonomic balance tips to parasympathetic dorsal vagalominance. The sharply decreased heart rate of bradycardia and

flaccid immobility (“playing dead”) signal this transition toollapse (Porges, 2011). The state of collapse is associated withgiving up” amid overwhelming excitation (Engel, 1978). It closelyverlaps with “mental defeat” (Ehlers et al., 2000). In the literature,lternate words for collapse include conservation-withdrawal,eath feigning, demobilization, faint, hyporesponsiveness, qui-scence, submission, syncope, and thanatosis. This plethora oferms reflects a fragmentation in our cultural awareness of the
noffensive state of collapse.
Table 1 lists the five defense states (Bracha, 2004) in order ofncreasing threat imminence (Fanselow and Lester, 1988; Lang

ioral Reviews 37 (2013) 1549–1566 1559

et al., 1997). For each state, autonomic activity (Porges, 2011),somatic or visceral manifestations, and experiential qualities aredescribed. The heart rate ranges presented are for typical adults.Distinct subjective experiences accompany different states andtheir transitions. Shame may arise from a history of collapse. Mov-ing from freeze-fright to an active defense in psychotherapy entailsdorsal vagal discharge (Levine, 1997; Scaer, 2001). Trembling andwarmth, at times sufficient to fog up a patient’s eyeglasses, canaccompany this discharge. Although not indicated in the Table, notethat defenses normally shift fluidly in response to changes in threatimminence, including changes in risk cues outside our awareness.

5.2. Defenses sometimes become disorganized

Shifts are not as fluid if defenses are dysregulated. Dysregula-tion entails inefficient or incomplete shifts between states, and itlimits access to more adaptive responses. For example, a rapidlyfluctuating heart rate may reflect oscillating sympathetic activityamidst strong dorsal vagal activation, as when freeze-fright vacil-lates with collapse. Favoring a well-used (or over-learned) defenseimpairs transitions to other states. Lack of resolution following evena single traumatic experience can generate extended wariness ora quick return to vigilance that persists for months or years. A his-tory of unresolved traumatizing experiences could easily sensitizeindividuals to the common aspects of these incidents, producing adefault state of freeze-alert that looks or feels like anxiety. In eithercase, the wariness of freeze-alert may extend to normal activitiesof daily living. Difficulty feeling safe when one is plainly in a safeenvironment is a common and unsettling indication of this type ofdysregulation.

Indeed, previously traumatized individuals with varied diag-noses and assessed under conditions of relative safety often doshow signs of the freeze-alert state (Austin et al., 2007; Dale et al.,2009; Hopper et al., 2006; Lampert et al., 2002; Lewis, 1940). Suchsigns include apprehensiveness in crowds and a tendency to takeoffense in response to uncertainty or if stressed. These responsesare consistent with prolonged hypervigilance and deficient cen-tral inhibition of responses to repetitive stimuli (Meares et al.,2011). Developmental or complex traumas often link sensitizationand immobility defenses through repeated conditioning; this coulddisorganize defenses over time. For example, a patient might expe-rience fear at her anger, or grow angry (with self) if afraid. Suchcomplications will be described elsewhere.

Attending to defense states, dysregulated or not, should giveresearchers a more nuanced understanding of stress responsesand enable clinicians to better diagnose trauma-related disorders.In nonlinear terms, the interplay of sympathetic and parasym-pathetic influences in defense states produce abrupt, saltatorytransitions, called bifurcations (Scherer, 2000; Weiner, 1992).Bifurcations mark qualitative shifts in either direction betweensafety and freeze-alert, between active defenses and freeze-fright,or between freeze-fright and collapse. Dysregulation implies sensi-tivity to initial conditions and long-term correlations (Heath, 2000;West, 2006). The psychophysical results of stressful experiencesmay extend well beyond symptoms of mental health. Stressful andtraumatizing experiences vary in severity and duration, and theycan occur one or many times. If left untreated, the consequencesof these events also grow more complex over time. The biologicaland psychological effects that follow repeated instances of stressand trauma can have profound implications for healthcare, asdescribed below.

6. What this means for healthcare researchers

Considering mental disorders to be rooted in the consciousmind, psychologists have approached these disorders beginning,

1560 D.V. Baldwin / Neuroscience and Biobehavioral Reviews 37 (2013) 1549–1566

Table 1Defense states: somatic, autonomic, and experiential aspects.

Defense state Somatic and visceralmanifestations

Autonomic activity Experiential/emotional aspects References

Safety (contrast) Relaxed; at ease. Upper faceand eyes animated; good eyecontact. Hearing tuned tospeech sounds. HR:60–80 bpm, with robust HRV

VVC dominant (vagal brake);SNS varies

Socially engaged; from quietand calm through activated.Capacity for speech, laughter,play, and tears. Able toself-soothe or seek socialsupport

Gottman (1999), Levensonet al. (1990), McCraty et al.(1995), Porges (2011), Rainvilleet al. (2006)

Freeze-alert (stillness) Body stillness. Eyes fixed.Muscles stiff and tense. Throattight, may “forget” to breathe.Rapid HR increase (to 85 or>90 bpm), with reduced HRV.Potentiated startle may initiatemovement

VVC decreased (vagalwithdrawal); SNS increases, ifprolonged

Alarm; stupefaction; wariness;early fear. Alert, watchfulwaiting; aware ofenvironment; sensitive to signsof danger. Able to movequickly if needed.

Austin et al. (2007), Leaton andBorszcz (1985), Ogden et al.(2006), Porges (2011),Sánchez-Navarro et al. (2006),Scherer et al. (2004), Vila et al.(2003)

Flight (active) Leg movements; turning, orbacking away. Decreaseddigestion. Fast respiration;sweating. HR > 100 bpm

SNS strong Fear or panic; restless. Impulseto run or warn others. Handsare cold

Ax (1953), Ekman et al. (1983),Gottman (1999), Gellhorn andLoofbourrow (1963), Leatonand Borszcz (1985), Perkinsand Corr (2006), Quarantelli(1954), Rainville et al. (2006)

Fight (active) Shoulder, arm, hand, and jawtense or clenched. Adrenalactivity with vasoconstriction.Fast respiration; sweating.HR > 100 bpm

SNS strong Anger or aggression, perhapswith anxiety. Impulse to kick,hit, or scream. Hands are warm

Ax (1953), Gellhorn andLoofbourrow (1963), Henry(1992), Levenson et al. (1990),McCraty et al. (1995), Ogdenet al. (2006), Perkins and Corr(2006), Rainville et al. (2006)

Freeze-fright (immobile) Body stillness. Eyes fixed.Stomach tension. Tonic (waxy)immobility. HR (∼100 bpm),pounding. Fast, shallow,intercostal breathing

DMX and SNS are both strong(coactive)

Hypervigilant. Fear or terror.Alert and aware, but feelsparalyzed, unable to move:scared stiff. May be separatedfrom sense of self

Fiszman et al. (2008), Gellhornand Loofbourrow (1963),Henry (1992), Koizumi et al.(1982), Levenson (1992), Marxet al. (2008), Porges (2011),Quarantelli (1954)

Collapse (immobile) Flaccid immobility (floppy);eyes averted or glazed.Bradycardia (HR ≤ 60 bpm),shallow slow breathing. Deathfeigning (playing dead).Syncope or death risk

Sharply reduced SNS (possiblyafter brief initial burst), leavesstrong DMX

Hopeless; giving up; surrender;shame. Detached, trancelikestate with impaired orienting.Numbness and analgesia(endogenous opioids)

Ehlers et al. (2000), Engel(1978), Hofer (1970), Nijenhuiset al. (1998), Porges (2011),Richter (1957)

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nd too often ending, with mental explanations. This strategy failshose who are suffering from issues induced or exacerbated bytress, especially when their symptoms look like affective disorders.n order to understand and treat trauma-related disorders properly

e need to recognize their psychobiological aspects. Addressingrimitive mechanisms that underlie disorders sensitive to stresshould increase the treatment possibilities for a wide range ofhronic diseases that currently resist healing. This includes someorms of hypertension or pain, and inflammatory disorders suchs heart failure or metabolic syndrome. Stress-related disordershould respond well to treatments that span the artificial lineetween the mental and the physical. Looking ahead, we could

ntegrate a systems biology approach, using personalized biomed-cal data to guide treatment and automated biofeedback to alternteroceptive conditioning in or below the brainstem. We couldocus on any defense reactions aroused by medical procedureshrough education or therapy, while also developing medicationspecifically targeted to facilitate progress (e.g., learning) within thesychotherapeutic process. These steps would boost treatment effi-acy and reduce costs.

A full recovery was unlikely for someone diagnosed with
rritable heart. Is it that much more certain now for soldiers retur-ing from multiple combat deployments or adults exposed to earlyhild abuse? The cost of treating traumatized individuals under-cores a continuing need to boost treatment efficiency. Recognition
rvous system; VVC, parasympathetic ventral vagal complex; DMX, parasympathetic

of trauma-related disorders as psychobiological might reduce thesocial stigma experienced by persons with these issues, and encour-age them to seek help earlier. Too often, adult survivors blamethemselves for becoming weak (immobile) when stressed, notrealizing that this now dysregulated defense began in childhoodwhen freeze-fright or collapse was their only viable option. A moreaccurate model of the range of defense states evoked in trauma-tizing experiences would help survivors better understand theirresponses, reducing needless distress. The following three sectionsdetail implications for stress research (Section 6.1), clinical practice(Section 6.2), and diagnostic nosology (Section 6.3).

6.1. Implications for stress research

Decoding how subcortical, cortical and peripheral areas interactand respond to escalating stress is a crucial task for researchers.Defense states provide a means to probe these links. Institutionalreview boards might be more apt to approve proposals for researchseeking to use moderate rather than extreme stressors, a bias thatpulls for active defenses and sympathetic activity. Studies that uti-lize moderately stressful events could still evoke unpredictable and
diverse defenses. Defenses vary when participants have unknownhistories of traumatization or if they display varied sensitivities toparticular kinds of stress. Immobility responses involve parasym-pathetic activity. Discriminating both freeze states and collapse

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equires differentiating between ventral vagal and dorsal vagalctivation. If only sympathetic activity is deemed relevant, thenreeze-fright is confused with fight or flight while collapse statesould easily be mistaken for tranquility or even rejected as

rtifact. This applies to stress research with any mammal, includ-ng humans. For example, animal researchers define the freezeesponse as a count or duration of observed motionlessness. Thiseliable measure potentially conflates three distinct immobilitytates, not only hindering attempts to delineate animal modelsor PTSD, but muddling efforts to study the stress responses of

ammals.People of different ages and genders likely have differing access

o defensive options. Varied PTSD symptoms and incidence rates,urrently attributed to age or gender status, might instead reflecthe unequal viability of defense states for persons in these groups.his alternative has not been examined. For example, Jacksont al. (2006) used skin conductance as a measure of the stressesponse and concluded that a prior stressful condition (similaro the Trier Social Stress Test) modulates fear conditioning differ-ntially in men and women. It might, but this study confoundsender with (mostly unmeasured) defenses. Skin conductance, aommon measure of the sympathetic stress response, does notapture ventral vagal withdrawal or dorsal vagal activation ando misses parasympathetic aspects of freeze-alert, freeze-fright,nd collapse. Jackson et al. used a single stressor and did noteasure vagal aspects of the stress response, so alternate expla-

ations remain viable. The genders may engage dissimilar defensetates to this or many stressors. Conditioning efficiency could varyith defense state, with gender, or with their interaction. These

esearchers found that men with higher salivary cortisol showednhanced fear conditioning even after their cortisol levels wereo longer elevated, although self-reported anxiety failed to pre-ict conditioning in men or women. Heightened cortisol impliesotivated performance against uncontrollable threats (Dickerson

nd Kemeny, 2004). Assessing all defensive responses acrossiverse stressors (with both sensitization and habituation), per-aps using a Brunswikian representative design, could clarify this

ssue.Researchers studying the heart under stress have two options.

hey can reject as artifact episodes of bradycardia from cardiac dataefore analysis. That option restricts, a priori, the ability to detectollapse in response to stressors. Alternately, they can analyze heartate data intact. This option increases variance that appears asoise, reducing statistical power to detect meaningful differences inesponse to changing levels of stress. Holmes et al. (2004) may havencountered the noise problem. In their study, carefully screenedissociative participants in control conditions watched a “traumaideo” of graphic traffic accidents and then recorded intrusions for

week thereafter. In two out of the three experiments they con-ucted, the average heart rates of 30 and 16 participants, recordednd synced to the film, slowed significantly (by 1.6 and 1.9 beatser minute [bpm]; standard deviation [SD] 2.49 and 3.08) as thearticipants viewed segments they subsequently recorded as intru-ive. These moments of peak distress were termed “hot spots”.he change in heart rate was akin to skipping a beat (Brewin, per-onal communication, 16 November 2004). Skipped beats mightndicate collapse or autonomic dysregulation: for instance, an inef-cient transition between defense states. In the third experiment,he average heart rate of 13 participants was 4.3 bpm slower dur-ng these hot spots, but that decrease did not reach significanceecause the variance tripled (SD 9.25). However, hot spots implyither freeze-fright or collapse, and combining those states would
harply increase variance. This speculation underscores a centraloint: Identifying and differentiating among the immobility states
s very difficult unless we assess their signature autonomic pat-erns.

ioral Reviews 37 (2013) 1549–1566 1561

6.2. Implications for clinical practice

Traumatizing events evoke defense states. Traumatized indi-viduals in states of freeze or collapse may appear quite still, butthe collapsed patients present as more flaccid or acquiescent andless tense or distressed. Mutual eye contact is most evident insafety. Gaze, normally fixed in either freeze state, averts in col-lapse. Patients in collapse might speak hopelessly of giving up. Theyregularly feel disgust, helplessness, or shame. Some report bodilyand emotional anesthesia (Nijenhuis et al., 1998). See Table 1 foradditional descriptions. Among patients with unrevealed traumahistories, however, defenses that masquerade as other disordershinder diagnosis. For example, when such patients readily shiftinto an immobility state they are unlikely to be identified as hav-ing shifted into a defense state linked to unresolved trauma. Busyhealthcare workers, unaware of a patient’s trauma history or itsrelevance, could confuse collapse with depression or either freezestate with anxiety. Reports of alternations among those statesmight suggest a history of bipolar episodes. In addition, treatingpatients solely with medications when they hold (unrecognized)trauma is unlikely to resolve their real issues. Thus, treatment effi-cacy can be unduly compromised when a traumatized person isincorrectly diagnosed with a disorder unrelated to stress. This biasseems particularly frequent in primary medical practices or inten-sive care units, where trauma-related symptoms are common andoften ignored (Davydow et al., 2008; Lecrubier, 2004; Neria et al.,2008).

The lesson for clinicians working with patients on knowntrauma issues is that effective psychotherapy requires recogniz-ing defense states as they emerge and shift. While experiencedtrauma therapists respond intuitively to signs of somatic acti-vation, teaching attunement to defense states certainly shouldadvance the training of trauma-informed clinicians. Primitivemechanisms respond well to unexpected interventions, such asEMDR (Ramachandran, 1995). Trauma-focused somatic aware-ness approaches can access and alter concomitant psychophysicalresponses. Relaxation aids in the processing of traumatic material(Elofsson et al., 2008), and should benefit dysregulated patients.Foa and Kozak (1986) found that numbing (suggesting collapse)impeded cognitive processing during trauma therapy. This appearsreasonable. The reduced cortical activity sometimes seen as trau-matized dissociative individuals reach collapse (Lanius et al.,2010) implies a lessened capacity to process information dur-ing stress. Managing defense-state shifts during psychotherapysessions and gearing specific interventions to distinct defensesrequires that clinicians adjust methods quickly. Interrupted activedefenses may need to complete, whereas boundary work, center-ing, and rehearsal of active coping skills while in a ventral vagal orfreeze-alert state could develop adaptive options prior to habitualcollapse (Brantbjerg, personal communication, 12 October 2008).Clearly, the considerations and clinical methods brought to bearin informed and trauma-focused psychotherapy diverge from andextend those used in cognitive-behavioral therapy or the originaltalking cure.

Attention to defenses provides a reliable definition of clinicalsuccess, since increased ventral vagal activity marks the return toa state of safety. However, research on treatment efficacy and theprocedural codes for psychotherapy sessions both fail to recognizesome unique features of trauma-informed therapy. First, evalu-ating treatment interventions with respect to specific diagnosticcategories is misguided and discards valuable data. Assessmentsof trauma-focused interventions need to account for defense
states. Specific defenses emerge under stress, with little regard fordiagnostic categories. When defense states do emerge, they canmoderate the effectiveness of medication (Fiszman et al., 2008).Notably, not one “evidence-based” psychotherapeutic approach

1 behav

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or trauma-related disorders has been evaluated for its efficacy inreating defense states. Hence, none can show evidence of efficacyith specific defenses. Second, concurrent physiological monitor-

ng assists in tracking real time shifts of autonomic states during aherapy session. Physiological monitoring clearly aids in diagnosis,ssessment, and treatment of patients with defense state involve-ent; e.g., it allows for contingent responses in virtual therapy

r by clinicians. Traumatized patients also benefit from extended∼90 min) sessions, to access dorsal vagal activation and allow timeor settling. However, some payers had denied previous Currentrocedural Terminology (CPT) codes for physiological monitorings experimental, or extended psychotherapy sessions as unneces-ary. CPT codes were revised for 2013, without input from traumarganizations. The current codes reduce session lengths. There iso code for a 90-min session, either with or without physiologicalonitoring.

.3. Implications for nosology

The comorbidities observed between traumatization and multi-le physical disorders are more closely associated with the degreef traumatization (including the number of lifetime traumas, orubthreshold PTSD) than with the PTSD diagnosis itself (Pietrzakt al., 2011; Sledjeski et al., 2008). Piecemeal explanations fail tolarify the scope or dynamics of associations with either symptomr comorbid forms of variability. Certainly, both internal (i.e., indi-idual; Griffin et al., 1997; Osuch et al., 2001) and external (e.g.,ypes of trauma, Herman, 1992a; Terr, 1991) factors are sources ofariability, but these static factors cannot fully explain either form.ather, both symptom variability and comorbid disorders appearo emerge from the varied reactions of entangled psychobiologicalurvival systems to diverse threats.

Several proposals to differentiate simple from more complexorms of PTSD (e.g., Ford, 1999; Herman, 1992a; Lanius et al., 2010;an der Kolk et al., 1996), based largely on differing prognoses andalient aspects of traumatic events, have yet to be incorporatedithin the DSM. Complex PTSD is associated with victims held cap-

ive or unable to flee during prolonged or repeated traumatizingxperiences. The prognosis of those diagnosed with Complex PTSDs poorer than it is for those with simple PTSD. From an evolution-ry perspective, it should be no surprise that Complex PTSD is theore difficult disorder to treat, since the defense states involved are

till virtually unrecognized. Simple PTSD arises from incompleter interrupted active defenses (i.e., sympathetic activity alone).omplex PTSD stems from freeze-fright or collapse (i.e., dorsalagal activation, with or without sympathetic activity). The pro-osed variants of PTSD appear to reflect distinct disorders arisingrom appropriately dissimilar responses to fundamentally differ-nt predicaments (danger vs. life-threat). Note that defense statesrovide a psychophysical structure for clinical distinctions such ashese.

An evolutionary outlook could provide a useful conceptualramework for stress-related disorders in the DSM (Bracha and

aser, 2008), which currently neglects mammalian defenses andreats similar symptoms as comparable whether they arise fromtress or not. The arousal symptoms in PTSD (Cluster E in the DSM-; APA, 2013) reflect sympathetic activation, but all defense statesxhibit arousal except for collapse. Some traumatizing incidentsngage active defenses that fail to complete. Others evoke immo-ility defenses. Repetition may entail autonomic dysregulation orven disorganization. Now, these cases are all combined in a singleisorder. Denoting stress-related symptoms and disorders in terms
f specific defenses would codify PTSD and other trauma-relatedisorders along evolutionarily relevant dimensions, increasingiagnostic sensitivity and perhaps revealing candidate endophe-otypes. The DSM-5 moved PTSD to a chapter on Trauma- and
ioral Reviews 37 (2013) 1549–1566

Stressor-Related Disorders and added a dissociative subtype (APA,2013). These are small but important steps forward. On the otherhand, as long as this diagnosis fails to recognize its underlying psy-chophysical dynamics, its symptoms seem to lack commonalityand we will continue to miss clinically meaningful expressions ofdistress.

7. Conclusions and perspective

Historically, the early trauma-related diagnoses emphasizedphysical signs. PTSD shifted the focus to mental signs, but prob-lems remain because trauma-related symptoms are inherentlypsychobiological. Psychoneuroimmunological data that describebidirectional communication among entangled survival systemsshed light on a false dichotomy; these data can advance our under-standing of comorbidity. Likewise, contemporary conceptions ofthe autonomic nervous system explain the diversity of observedsymptom variability. A balanced appreciation of the psychophysi-cal contributions to trauma symptoms will only emerge as we seesymptoms in the light of current facts.

Traumatizing experiences tap defensive responses associatedwith danger and life-threat. Viewing trauma within an evolution-ary framework respects peripheral influences, and accepts a widerange of defensive behaviors. These diverse reactions to trauma andthe varied symptoms in trauma-related disorders appear anoma-lous outside of their evolutionary context. Variance associated withdefense state transitions is well suited for nonlinear analyses in twoways. First, autonomic parameters constrain bifurcations amongdefense states. Second, their complex oscillations are dynamic,entangled, recurring, and sensitive to initial conditions. Attendingto the full range of defensive options will deepen our understandingof these variable responses to stress. The historical controversiesover clinical approaches to managing trauma, as well as disagree-ments over the efficacy of trauma-focused interventions, mighthave stemmed from variability in the heretofore-undelineateddefensive states of patients.

New perceptions can change the meaning of well-known facts(Hanson, 1961). Barrett (2006) argues that naive assumptions havespread confusion and hobbled the study of emotion. The traumatic-stress field could be ripe for a similar re-conceptualization. Bypointing out the consequences of narrow premises, I hope to turnattention toward some primitive mechanisms that are involvedwhen stress induces or exacerbates diverse symptoms. Scienceusually advances by gradually accreting new data, but accom-modating fresh ideas brings a different kind of progress (Kuhn,1970). Scientific ideas gain credibility when they allow researchersto solve important problems. An evolutionary perspective offersreal solutions because it sees both phylogenetic and psychobio-logical influences on trauma-related disorders. This broader viewcould guide not just approaches to biopsychosocial treatment, butapproaches to research.

Acknowledgments

Many patients over many years have generously described theirexperiences, providing invaluable insights into their diverse reac-tions and responses to traumatic events. I am also grateful to JulianFord, Ellert Nijenhuis, Steve Porges, Onno Van der Hart and BruceWest for comments on prior versions, and to Don Tucker for hisencouragement and patience.

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Neuroscience and Biobehavioral Reviews · The symptoms we identify and the behaviors we recognize as defenses deﬁne which symptoms we see as trauma-related. Early conceptions of